EP2398779B1 - New process for the preparation of nitroorotic acid - Google Patents

New process for the preparation of nitroorotic acid Download PDF

Info

Publication number
EP2398779B1
EP2398779B1 EP10711860.6A EP10711860A EP2398779B1 EP 2398779 B1 EP2398779 B1 EP 2398779B1 EP 10711860 A EP10711860 A EP 10711860A EP 2398779 B1 EP2398779 B1 EP 2398779B1
Authority
EP
European Patent Office
Prior art keywords
acid
process according
nitroorotic
nitric acid
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP10711860.6A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2398779A1 (en
Inventor
Rolf Dach
Xiangrui Jiang
Jingshan Shen
Jin Suo
Yi Zhu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Priority to PL10711860T priority Critical patent/PL2398779T3/pl
Publication of EP2398779A1 publication Critical patent/EP2398779A1/en
Application granted granted Critical
Publication of EP2398779B1 publication Critical patent/EP2398779B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Subject of the present invention is a new process for the preparation of nitroorotic acid (II), which is obtained by nitration of orotic acid (I) according to the following reaction scheme:
  • Nitroorotic acid is a key intermediate in the synthesis of dipyridamole, which is an active ingredient in Persantin ® (sole active ingredient) and Aggrenox ® (in combination with acetylsalicylic acid).
  • Persantin ® is a medicament used for preventing thrombosis and embolic events
  • Aggrenox ® is a medicament used for the prevention of stroke.
  • the patent DD 126 811 describes a synthesis of 5-nitrouracilcarboxylic acid-(4) (nitroorotic acid) starting from 4-methyluracil.
  • the starting material is nitrated using concentrated nitric acid to give the intermediate 4-methyl-5-nitrouracil, which is then oxidized without prior isolation by adding more concentrated nitric acid to yield nitroorotic acid.
  • the nitroorotic acid needed for the manufacture of Persantin is produced by a large scale process based on nitration and oxidation of 6-methyluracil using fuming nitric acid.
  • the reaction temperature has to be maintained in a range of between 20°C and 30 °C.
  • the oxidation step requires a temperature of up to 100°C.
  • the whole reacation system may become instable, if the temperature is not controlled properly.
  • the technical measurements, which are needed to regulate the system and to control the temperature in order to avoid e.g. decomposition, are highly expensive.
  • the maximum yield of the current process is about 80% of the theory.
  • a byproduct of this process is nitrogen dioxide, a toxic gas. For each mole of the starting material 6-methyluracil, 6 moles of nitrogen dioxide are set free, which have to be disposed of properly.
  • the aim of the present invention is to overcome the problems linked to the present process for producing nitroorotic acid, to improve the known process for preparing nitroorotic acid, particularly with respect to both economic (yield, costs and availability of starting material) and ecological (protection of the environment) aspects of a large scale process, and to enhance the safety (protection of employees) of the process.
  • Subject of the present invention is a new improved process for the preparation of nitroorotic acid via nitration of orotic acid according to reaction scheme 1.
  • the educt is readily available in good quality and at a reasonable price, because it is widely used (several 100 tons per year) as an ingredient for animal food.
  • the reagents are very common and in expensive chemicals, too, so that the costs of goods are low.
  • reaction temperature is significantly lower than in the process known from the prior art. Furthermore, due to the lower reaction temperature particularly during the oxidation step, no expensive technical measurements for system regulation and temperature contronl are needed.
  • the process of invention does not require any special equipment for controlling the reaction due to safety issues.
  • Another advantage of the process according to the invention is that it can be conducted as a semi-batch process, i.e. that the educt (orotic acid) does not need to be added all at once, but may be added portionwise to the mixture of sulphuric and nitric acid. The next portion of orotic acid is added to the reaction mixture only after the previous portion was transformed into the product. This procedure, which was not possible according to the old method, helps to control the reaction in a simple, but effective way. Energy (and temperature) peaks can thus be avoided.
  • the nitroorotic acid can be isolated as free acid, and thus, does not need to be set free from its salt prior to the next reaction step in the synthesis of dipyridamole, thereby avoiding additional working steps and saving time. Furthermore, after quenching the reaction mixture in water, the water-containig product thus obtained may be used directly in the next step without that it is necessary to dry it previously, thereby saving time and costs. Due to the very high purity, the product of the subsequent step in the synthesis of dipyridamole does not need to be isolated.
  • the sulphuric acid used in the reaction can be recycled directly, after concentration. This is both reducing costs and protecting the environment.
  • Nitroorotic acid (II) is produced by nitration of orotic acid (I) according to reaction scheme 1.
  • a mixture of concentrated sulphuric acid and concentrated (but not fuming) nitric acid is used as the reagent.
  • the concentration of the sulphuric acid is 98 % and the concentration of the nitric acid is 65 %.
  • sulphuric acid and nitric acid are mixed in a molar ratio of between 1:1 and 6:1.
  • the ratio of sulfuric acid to nitric acid is about 3:1 (in mole).
  • the nitration is carried out at a temperature of about 40-80 °C.
  • the preferred reaction temperature is about 40 - 60 °C; even more preferrd is a reaction temperature of about 50 - 60°C.
  • the nitroorotic acid such produced is susceptible to form hydrates.
  • Nitroorotic acid obtained via nitration of orotic acid
  • 420 ml (7.68 mol) concentrated sulphuric acid H 2 SO 4 . approx.. 98%) were added to 169 ml (2.56 mol) 65 % nitric acid (HNO 3 ).
  • 200 g orotic acid (1.28 mol; purity 99.64 %) were added portionwise.
  • the reaction mixture was heated to 50 - 55°C under stirring for 3 hours. After completion of the nitration, the reaction mixture was allowed to cool down to ambient temperature (about 10 -15°C), and was then poured into 800 ml of water under cooling below 30°C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP10711860.6A 2009-02-23 2010-02-22 New process for the preparation of nitroorotic acid Active EP2398779B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PL10711860T PL2398779T3 (pl) 2009-02-23 2010-02-22 Nowy sposób wytwarzania kwasu nitroorotowego

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910007568A CN101812023A (zh) 2009-02-23 2009-02-23 制备硝基乳清酸的新方法
PCT/EP2010/052188 WO2010094791A1 (en) 2009-02-23 2010-02-22 New process for the preparation of nitroorotic acid

Publications (2)

Publication Number Publication Date
EP2398779A1 EP2398779A1 (en) 2011-12-28
EP2398779B1 true EP2398779B1 (en) 2013-12-18

Family

ID=42125911

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10711860.6A Active EP2398779B1 (en) 2009-02-23 2010-02-22 New process for the preparation of nitroorotic acid

Country Status (8)

Country Link
US (2) US8513413B2 (ja)
EP (1) EP2398779B1 (ja)
JP (1) JP5611244B2 (ja)
CN (3) CN101812023A (ja)
DK (1) DK2398779T3 (ja)
ES (1) ES2444519T3 (ja)
PL (1) PL2398779T3 (ja)
WO (1) WO2010094791A1 (ja)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102702114B (zh) * 2012-05-28 2014-12-17 浙江海正化工股份有限公司 一种硝基乳清酸的制备方法
CN110452180A (zh) * 2019-06-25 2019-11-15 南京普锐达医药科技有限公司 一种合成2-氯-5-氨基-6-嘧啶甲酸乙酯的方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH592636A5 (ja) * 1975-01-13 1977-10-31 Lonza Ag
DD126811B1 (de) * 1976-07-29 1980-12-24 Herbert Goldner Verfahren zur herstellung von 5-nitrouracilcarbonsaure-(4)

Also Published As

Publication number Publication date
US8513413B2 (en) 2013-08-20
JP2012518620A (ja) 2012-08-16
CN101812023A (zh) 2010-08-25
DK2398779T3 (da) 2014-02-10
EP2398779A1 (en) 2011-12-28
PL2398779T3 (pl) 2014-05-30
JP5611244B2 (ja) 2014-10-22
CN104098576A (zh) 2014-10-15
US20130303760A1 (en) 2013-11-14
WO2010094791A1 (en) 2010-08-26
CN102307864B (zh) 2014-07-09
CN104098576B (zh) 2016-03-30
ES2444519T3 (es) 2014-02-25
US20120123118A1 (en) 2012-05-17
CN102307864A (zh) 2012-01-04

Similar Documents

Publication Publication Date Title
EP3476837B1 (en) Method for preparing azoxystrobin intermediates
EP3366666B1 (en) Preparation method for aryl-substituted p-phenylenediamine substance
EP2200978A1 (de) Verfahren zur herstelung von sulfonsäurediamiden
EP2537829B1 (de) Aminobenzoylsulfonsäureamide und deren Herstellung
Rousseau et al. Structure and Ultraviolet Absorption Spectra of Indazole, 3-Substituted Indazole and Some of Their Derivatives1
EP2398779B1 (en) New process for the preparation of nitroorotic acid
CN111662184A (zh) 一种啶酰菌胺中间体2-(4’-氯苯基)苯胺的合成方法
US20040199012A1 (en) Method and apparatus for preparing hydrazo-dicarbonamide using urea as starting material
DE3327824A1 (de) Verfahren zur herstellung von n,o-substituierten mono- und/oder polyurethanen
JPH0246575B2 (ja)
CN110218192B (zh) 一种2-氨基-4,6-二甲氧基嘧啶的制备方法
JPS6342616B2 (ja)
JPS6412266B2 (ja)
DE2942510A1 (de) Verfahren zur herstellung von aryl-mono- und -polyurethanen
US5319133A (en) Isocyanates and their preparation using hypochlorous acid
CN110218177B (zh) 一种2,6-二氯-3-硝基吡啶的制备方法
RU2198877C1 (ru) Способ получения 2-метил-4(5)-нитроимидазола
US2538907A (en) Preparation of nitroxyethyldinitro-guanidine
CN110818643A (zh) 一种2-氨基-4,6-二甲氧基嘧啶的制备方法
US5233083A (en) Process for the preparation of 2-amino-3-chlorobenzoic acid
JP2003503393A (ja) 酸クロライドを用いて４，６−ジクロロピリミジンを製造する方法
CN118772022A (zh) 一种n-甲基-n-异丙基胺基磺酰胺的制备方法
JPH08504787A (ja) ヒドロキシルアミンエーテルおよびその塩の製造方法ならびにそのための中間生成物
JPH02233649A (ja) ２‐ニトロ‐４‐トリフルオロメチルアニリンの製造方法
JPS61151165A (ja) ポリチオビスフエノ−ルの製法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110923

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20130717

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE PATENT HAS BEEN GRANTED

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 645571

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140115

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Effective date: 20140204

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602010012508

Country of ref document: DE

Effective date: 20140213

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2444519

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20140225

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140318

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140418

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140418

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602010012508

Country of ref document: DE

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E020491

Country of ref document: HU

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140222

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20140919

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602010012508

Country of ref document: DE

Effective date: 20140919

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140319

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20170216

Year of fee payment: 8

Ref country code: CH

Payment date: 20170217

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20170216

Year of fee payment: 8

Ref country code: BE

Payment date: 20170216

Year of fee payment: 8

Ref country code: PL

Payment date: 20170217

Year of fee payment: 8

Ref country code: AT

Payment date: 20170217

Year of fee payment: 8

Ref country code: HU

Payment date: 20170213

Year of fee payment: 8

Ref country code: NL

Payment date: 20170216

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20170213

Year of fee payment: 8

Ref country code: IT

Payment date: 20170221

Year of fee payment: 8

Ref country code: TR

Payment date: 20170214

Year of fee payment: 8

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20131218

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20180228

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20180301

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 645571

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180223

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180223

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20180228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180228

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180228

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180301

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180228

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180222

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180228

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20190801

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180223

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180222

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180222

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20240219

Year of fee payment: 15

Ref country code: GB

Payment date: 20240219

Year of fee payment: 15

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20240221

Year of fee payment: 15